As highlighted in the data on the global epidemiology of dyslipidemia and burden of cardiovascular disease, there is considerable variation in dyslipidemia-related ASCVD risk across countries. Thus, the anticipated benefits in terms of CVD prevention as a consequence of effective implementation of either population-wide lifestyle change strategies or treatment of high risk individuals with cholesterol-lowering medication differ across ethnically and culturally heterogeneous populations.  Newly updated guidelines for most countries have been published after 2015 and are therefore based on relatively recent research evidence to provide time-sensitive guidance. Clinical guidelines have an essential role in guiding clinical practice by providing physicians with recommendation based on these latest data. As a guide to management strategies, there are some similarities in the guidelines issued by Western and non-Western countries.

All guidelines support lifestyle modification as an effective method to manage lipid level. Most clinical guidelines across countries recommend treatment strategies as a function of CVD risk assessment and untreated LDL-C levels for the purpose of keeping LDL-C within the specific target values. Almost all guidelines recommend LDL-C as the primary treatment target, and non-HDL-C and/or apolipoprotein B as the secondary treatment target [19,20,21,23,24,27,30,34]. Additionally, statins are the first-line agents in all guidelines. The addition of ezetimibe is recommended by most countries when the LDL-C goal is not achieved with the maximum tolerated dose of statins. Due to the successes of recent clinical trials, PCSK9 inhibitors are also recommended in some guidelines [19,21,24,27,28,29,30,34]. Besides the two nonstatin widely recommended in some guidelines, bile acid sequestrants may be considered as an add-on drug with statins to reduce LDL-C. Fibrates are recommended to lower triglyceride levels [21,23,24,25,27,28,29,30,34], but there are still no trials to show the cardiovascular benefit of fibrates except for meta-analysis of high triglyceride and low HDL-C groups [36], and recently the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes study has been discontinued as pemafibrate was reported to be unlikely to reduce CVD risk [37]. Additionally, niacin is recommended for treatment of hypertriglyceridemia in some guidelines, yet this agent is not recommended in combination with statin therapy due to a lack of additional benefits for CVD prevention in patients who have achieved LDL-C goals [29,30]. Pure eicosapentaenoic acid (EPA) can lower CVD risk in persons with moderately high triglyceride levels on statin therapy, which is the conclusion of the Japan EPA Lipid Intervention Study and the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial [38,39]. Icosapent Ethyl is recommended to be used in combination with statins for specific patients with moderately high triglyceride levels in some guidelines [23,34]. Many agents for dyslipidemia treatment are under study. For example, acyl-coenzyme A: cholesterol acetyltransferase (ACAT) inhibitor was reported to decrease cholesteryl ester accumulation in macrophages in animal studies [40]. However, randomized controlled trials (RCT) using non-selective ACAT inhibitors failed to show benefits in the changes in coronary atheroma volume and carotid intima-media thickness [40], and no evidence from RCT for CVD outcomes is available.

However, some differences are also observed between guidelines issued by different countries and organizations at various time points. First, risk assessments are based on different lists of risk factors in different guidelines, even though some of the risk factors have neither enough data for CVD risk prediction and have not been evaluated in most risk-predictive models, nor an available interventional approach. As reported in the previous review on cardiovascular risk assessment [41], among the 10 guidelines on dyslipidemia, the risk-factor list ranged from five risk factors (including age, sex, systolic blood pressure, TC, and smoking) to 13 risk factors. Second, these guidelines recommend different algorithms to categorize CVD risk, which might be based on considerations of feasibility and practicability in local practice. An exponential model including 186 countries evaluated that using the same CVD risk estimation to initiate statins use, irrespective of age, sex, and country, is not appropriate globally. Considering current characteristics of the national population and safety in medication treatment to determine treatment strategy might be the optimal solution [42]. Third, different guidelines recommended different definitions of ‘high risk’. The varying recommendations for risk assessment among country-specific guidelines are generally central to treatment decision-making in clinical practice. However, these notable differences in the definition of high risk between guidelines may lead to an individual categorizing in a completely different risk bracket according to different guidelines developed by different organizations in different countries or regions, or even different guidelines developed in the same country or region. Fourth, the LDL-C treatment goals are also different among guidelines recommended by a comprehensive cardiovascular risk reduction strategy. In the 2019 European Society of Cardiology (ESC) / European Atherosclerosis Society (EAS) guidelines for the management of dyslipidemias [34], the LDL-C target goal is <55 mg/dL for individuals with very high risk in primary or secondary prevention. In patients with ASCVD who experienced a second vascular event within 2 years, it is recommended to lower LDL-C to less than 40 mg/dL (Table S1), which is consistent with the recommendations for patients who have extreme risk of Polish Lipid Association published in 2021 [27]. This further risk stratification for patients with ASCVD is considered in more and more countries.

The initial doses of statins recommended by the guidelines also differ. Most country-specific guidelines recommend the dose of statins should be based on baseline ASCVD risk and expected LDL-C reduction of that risk [22,24,27,28,35], while some countries only mentioned the initial dose in very high and high risk individuals [25,26]. High-intensity statins or a maximally tolerated dose of statins are the most common therapeutic dose for individuals with very high and/or high CVD risk [20,21,25,30,32,33,34]. Moderate-intensity statins are recommended in Chinese guideline considering the safety of the high-intensity statins in the Chinese population [19].

Another aspect that merits special concern is the screening for genetic dyslipidemias. For example, as an important type of genetic dyslipidemias, screening for familial hypercholesterolemia (FH) has been recommended by the guidelines issued by the American Association of Clinical Endocrinologists and American College of Endocrinology, the National Institute for Health and Care Excellence, Japan Atherosclerosis Society, the Chinese Society of Cardiology and Philippine Heart Association [19,20,23,24,25,28,29,30,33,34,35]. However, the majority of national guidelines worldwide have no such recommendation, leaving room for enhanced detection of FH.

Inconsistencies in the recommendations for the management of dyslipidemia might be a contributing factor to low implementation in clinical practice. Additionally, for some countries in most parts of Africa and Eastern Europe, no local clinical practice guidelines exist for dyslipidemia.

For the global population, advocating a healthy lifestyle, understanding the harm of dyslipidemia, and preventing the occurrence of dyslipidemia in early stages are the cornerstones of ASCVD prevention. For individuals with a high risk of ASCVD and patients with established ASCVD, the key point is to ensure the use of lipid-lowering drugs and improve the treatment and control rate of dyslipidemia. However, the treatment and control rates show great differences across various countries.

Substantial decreases in non-HDL-C levels and subsequent reductions in the ASCVD burden in high-income Western countries during the past 30 years were partly owing to the contribution of lipid-lowering therapy. One study used data from the National Health and Nutrition Examination Survey from 2011 to 2012 and found that the treatment and control rate of dyslipidemia in the United States of America (USA) reached 54.1% and 66.0%, respectively [43]. The use of lipid-lowering drugs, especially statins has increased, which may be attributable to the availability of generic statins and reduced drug prices in health care systems. A retrospective longitudinal cohort study conducted from 2002 to 2013 in 157,000 adults aged 40 years and older in the USA [44] demonstrated that statins use in the general population increased 79.8%, especially the proportion of generic statins, from 8.4% in 2002–2003 to 81.8% in 2012–2013. However, the uptake of statins was suboptimal among patients with established ASCVD, at 49.8% in 2002–2003 and 58.1% in 2012–2013. The total expenditures and out-of-pocket expenditures associated with statins decreased, and further substitution of brand-name statins to generic statins may yield greater savings. In addition to the cornerstone role of statins in reducing ASCVD risk, the role of lipid lowering treatment beyond statins cannot be ignored. There is considerable evidence supporting the benefits of nonstatin cholesterol-lowering medications in combination with statins, especially cholesterol absorption inhibitors (ezetimibe) and PCSK9 inhibitors [45,46]. Nonstatin use in the USA adult population has also increased by 124%, from 2.5% in 2002–2003 to 5.6% in 2012–2013, and 15.9% of high-intensity statin users also used nonstatin in 2012–2013 [47].

By contrast, among countries in East and Southeast Asia (for example, China and Malaysia) that have had substantial increases in non-HDL-C levels and dyslipidemia-related ASCVD risk over the past 30 years, the treatment and control rates are unsatisfied. In the China Chronic Disease and Risk Factor Surveillance conducted among 163,641 Chinese adults aged > 18 years from 2013 to 2014, 11.2% were at high or very high risk of ASCVD. Among them, 74.5% individuals with high risk and 93.2% individuals with very high risk did not achieve their LDL-C lowering targets. Among the population with high and very high ASCVD risk that did not achieve their LDL-C lowering targets, only 5.5% and 14.5% received lipid-lowering drugs, respectively [48]. Although several studies have shown that the rate of statin utilization in Chinese patients with acute myocardial infarction during hospital admission has improved substantially in recent years [49], low adherence of statin use was found after discharge. A nationwide registry study with 192 participating hospitals from 2014 to 2018 among 6523 Chinese patients with acute coronary syndrome and a history of myocardial infarction or revascularization found that 50.8% were receiving lipid-lowering therapy before hospitalization (statin monotherapy in 98.4%, combination therapy in 1.2%), and only 30.1% of patients had LDL-C < 70 mg/dL at admission [50]. These studies suggest that statins use is inadequate in these regions. This seems to be related to many factors, including the availability and affordability of medications in hospitals or clinics at different levels, quality of care from medical service providers, and adherence to treatment by patients. The availability of medications is of utmost importance. One nationwide study assessed the availability of lipid-lowering medications in a survey of 3041 primary care institutions from 2016 to 2017, which included 145 community health centers, 384 community health stations from urban areas, 243 township health centers, and 2269 village clinics from rural areas in 31 Chinese provinces [51]. The availability of statins at these primary care institutions was only 49.7%, and village clinics had the lowest statin availability (43.7%) among the four types of institutions. This study was the first to address this important issue in a nationwide survey in these regions. The marked deficiencies in statins availability at primary care institutions are not consistent with the health needs of the population and have implications for patients’ health, which may mostly restrict the impact of lipid-lowering medication on reducing the CVD burden. Except concerning the marked underuse of lipid-lowering drugs for those meeting treatment criteria, more importantly, lipid-lowering therapy would certainly result in a higher economic burden from a public health perspective. In Western countries, statins therapy is cost-effective or cost-saving, especially in people with high CVD risk [52,53,54]. In China, with the intervention of government policy in recent years, the cost-effectiveness of lipid-lowering medication has significantly improved in Chinese population [55,56].

Effective community-based prevention strategies that promote lifestyle modification (e.g., dietary improvement and regular physical activity) are also needed to control dyslipidemia in the whole population and prevent the occurrence of dyslipidemia at an early stage. Understanding dyslipidemia related CVD risk and regular monitoring of blood lipids is also crucial. A large survey from 2007 to 2010 conducted in 43,368 Chinese adults aged ≥ 18 years reported that the awareness rate for dyslipidemia was 31.01% [57]. These data suggest the need to raise awareness of dyslipidemia among the general population and clinicians and increase the capacity of primary care institutions to screen and diagnose dyslipidemia in community residents.